A synthetic glucagon-like peptide-1 analog with improved plasma stability

in Journal of Endocrinology
Authors:
U Ritzel
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U Leonhardt
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M Ottleben
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A Ruhmann
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K Eckart
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J Spiess
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G Ramadori
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DOI:
https://doi.org/10.1677/joe.0.1590093
Volume/Issue:
Volume 159: Issue 1
Article Type:
Other
Page Range:
93–102
Online Publication Date:
01 Oct 1998
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Glucagon-like peptide-1 (GLP-1) is the most potent endogenous insulin-stimulating hormone. In the present study the plasma stability and biological activity of a GLP-1 analog, [Ser]GLP-1(7-36)amide, in which the second N-terminal amino acid alanine was replaced by serine, was evaluated in vitro and in vivo. Incubation of GLP-1 with human or rat plasma resulted in degradation of native GLP-1(7-36)amide to GLP-1(9-36)amide, while [Ser]GLP-1(7-36)amide was not significantly degraded by plasma enzymes. Using glucose-responsive HIT-T15 cells, [Ser]GLP-1(7-36)amide showed strong insulinotropic activity, which was inhibited by the specific GLP-1 receptor antagonist exendin-4(9-39)amide. Simultaneous i.v. injection of [Ser]GLP-1(7-36)amide and glucose in rats induced a twofold higher increase in plasma insulin levels than unmodified GLP-1(7-36)amide with glucose and a fivefold higher increase than glucose alone. [Ser]GLP-1(7-36)amide induced a 1.5-fold higher increase in plasma insulin than GLP-1(7-36)amide when given 1 h before i.v. application of glucose. The insulinotropic effect of [Ser]GLP-1(7-36)amide was suppressed by i.v. application of exendin-4(9-39)amide. The present data demonstrate that replacement of the second N-terminal amino acid alanine by serine improves the plasma stability of GLP-1(7-36)amide. The insulinotropic action in vitro and in vivo was not impaired significantly by this modification.

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Print ISSN:
0022-0795
Online ISSN:
1479-6805
Page(s):
10
Article Type:
Other
Print Publication Date:
01 Oct 1998
Online Publication Date:
01 Oct 1998